Biotechnology and Bioprocess Engineering 2021; 26(6): 985-992  
Structural Study on the Impact of S239D/I332E Mutations in the Binding of Fc and FcγRIIIa
Petrina Jebamani, Dinesh Kumar Sriramulu, Sang Taek Jung, and Sun-Gu Lee
Petrina Jebamani, Dinesh Kumar Sriramulu, Sun-Gu Lee*
Department of Chemical Engineering, Pusan National University, Busan 46241, Korea
Tel: +82-51-510-2786
E-mail: sungulee@pusan.ac.kr
Sang Taek Jung*
Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul 02841, Korea
Tel: +82-2-2286-1422
E-mail: sjung@korea.ac.kr
Received: January 29, 2021; Revised: March 23, 2021; Accepted: March 23, 2021; Published online: December 31, 2021.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Engineering of Fc for improved affinity to its receptor, FcγRIIIa, can enhance the therapeutic activity of monoclonal antibodies. S239D/I332E mutation of Fc has been extensively employed in various Fc engineering studies. Still, it is not clear how the mutations have structurally influenced the molecular interactions between Fc and FcγRIIIa. In this study, the point or combined mutations of S239D/I332E were introduced into one chain (A) or the other chain (chain B) of the homodimeric Fc domain computationally. Their structural effects on the binding to FcγRIIIa were investigated through a computational docking method. These results showed that the chain-specific point mutation, S239D induced a new salt-bridge with the receptor in A and B chains of Fc, whereas I332E mutation generated a new salt-bridge with the receptor only in A chain. The combined mutation study identified that the Fc variant with four mutations reproduced the three salt-bridges. This showed that the mutation of S239D and I332E in chain A of Fc induced complex salt-bridge formation with the Lys158 of FcγRIIIa. This study is expected to provide more structural insight into Fc variants’ design based on S239D/I332E mutation.
Keywords: Fc, FcγRIIIa, in silico mutation, protein-protein docking, salt-bridges


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